20-44625581-G-T

Variant names:

• chr20-44625581-G-T
• NM_000022.4:c.466C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000022.4(ADA):​c.466C>A​(p.Arg156Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R156C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADA NM_000022.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.57

Genes affected

ADA (HGNC:186): (adenosine deaminase) This gene encodes an enzyme that catalyzes the hydrolysis of adenosine to inosine in the purine catabolic pathway. Various mutations have been described for this gene and have been linked to human diseases related to impaired immune function such as severe combined immunodeficiency disease (SCID) which is the result of a deficiency in the ADA enzyme. In ADA-deficient individuals there is a marked depletion of T, B, and NK lymphocytes, and consequently, a lack of both humoral and cellular immunity. Conversely, elevated levels of this enzyme are associated with congenital hemolytic anemia. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-44625581-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 20-44625581-G-T is Pathogenic according to our data. Variant chr20-44625581-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3251901.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADA	NM_000022.4	c.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 12	ENST00000372874.9	NP_000013.2
ADA	NM_001322051.2	c.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 11		NP_001308980.1
ADA	NM_001322050.2	c.73+875C>A		intron_variant	Intron 4 of 10		NP_001308979.1
ADA	NR_136160.2	n.558C>A		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADA	ENST00000372874.9	c.466C>A	p.Arg156Ser	missense_variant	Exon 5 of 12	1	NM_000022.4	ENSP00000361965.4
ADA	ENST00000695995.1	c.217-2503C>A		intron_variant	Intron 3 of 8			ENSP00000512318.1
ADA	ENST00000695991.1	c.217-2651C>A		intron_variant	Intron 3 of 7			ENSP00000512314.1
ADA	ENST00000696038.1	n.*212C>A		non_coding_transcript_exon_variant	Exon 5 of 9			ENSP00000512344.1
ADA	ENST00000696038.1	n.*212C>A		3_prime_UTR_variant	Exon 5 of 9			ENSP00000512344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1429860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708270

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Severe combined immunodeficiency disease Pathogenic:1

Apr 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADA c.466C>A (p.Arg156Ser) results in a non-conservative amino acid change located in the adenosine deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 202092 control chromosomes. To our knowledge, no occurrence of c.466C>A in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. Different variants affecting the same codon has been classified as pathogenic by our lab (c.466C>T, p.Arg156Cys; c.467G>A, p.Arg156His), supporting the critical relevance of codon 156 to ADA protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.92		Loss of MoRF binding (P = 0.0148);Loss of MoRF binding (P = 0.0148);
MVP		0.96
MPC		0.67
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-43254222;